Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol
Ruiyang Gao, Bei Yue, Cheng Lv, Xiaolong Geng, Zhilun Yu, Hao Wang, Beibei Zhang, Fangbin Ai, Ziyi Wang, Ziyi Wang, Donghui Liu, Zhengtao Wang, Zhengtao Wang, Kaixian Chen, Wei Dou
Abstract
Irinotecan (CPT11) chemotherapy-induced diarrhea affects a substantial cancer population due to β -glucuronidase (Gus) converting 10- O -glucuronyl-7-ethyl-10-hydroxycamptothecin (SN38G) to toxic 7-ethyl-10-hydroxycamptothecin (SN38). Existing interventions primarily address inflammation and Gus enzyme inhibition, neglecting epithelial repair and Gus-expressing bacteria. Herein, we discovered that dehydrodiisoeugenol (DDIE), isolated from nutmeg, alleviates CPT11-induced intestinal mucositis alongside a synergistic antitumor effect with CPT11 by improving weight loss, colon shortening, epithelial barrier dysfunction, goblet cells and intestinal stem cells (ISCs) loss, and wound-healing. The anti-mucositis effect of DDIE is gut microbiota-dependent. Analysis of microbiome profiling data from clinical patients and CPT11-induced mucositis mice reveals a strong correlation between CPT11 chemotoxicity and Gus-expressing bacteria, particularly Enterococcus faecalis ( E. faecalis ). DDIE counters CPT11-induced augmentation of E. faecalis , leading to decreased intestinal Gus and SN38 levels. The Partial Least Squares Path Model (PLS-PM) algorithm initially links E. faecalis to dysregulated epithelial renovation. This is further validated in a 3D intestinal organoid model, in which both SN38 and E. faecalis hinder the formation and differentiation of organoids. Interestingly, colonization of E. faecalis exacerbates CPT11-induced mucositis and disturbs epithelial differentiation. Our study unveils a microbiota-driven, epithelial reconstruction-mediated action of DDIE against mucositis, proposing the ‘Gus bacteria–host–irinotecan axis’ as a promising target for mitigating CPT11 chemotoxicity. Dehydrodiisoeugenol (DDIE) alleviates CPT11-induced intestinal mucositis alongside a synergistic antitumor effect with CPT11. The Gus-expressing Enterococcus faecalis -mediated dysregulation of intestinal epithelial regeneration in CPT11-treated mice is counteracted by DDIE.